Microbial organisms and their components have long been known to affect the immune systems of mammals. Infection with virulent bacteria and viruses can cause severe illness or death. Contributing toward this, purified components of bacteria and viruses can also cause pathology by inducing inflammatory responses or otherwise causing the immune system to behave in an undesirable manner. Despite this, vaccines including whole bacteria, viruses, or parts thereof have not only proven to be one of the most powerful tools that medicine has developed to prevent serious infections, but also can cause other beneficial effects. For example, in experimental models, a live attenuated pertussis vaccine candidate named BPZE1 (see WO2007104451A1) was found to not only protect against virulent Bordetella pertussis, but also to exert potent anti-allergic and anti-asthma effects by dampening hyperimmune responses to allergens (see WO2013066272A1).
Developing safe and effective vaccines nonetheless remains challenging for several reasons. Among these, despite modern molecular biology techniques and significant advances in our understanding of microbiology and immunology, it remains quite difficult to produce a vaccine product that is sufficiently attenuated to not cause significant pathology, while at the same time sufficiently immunogenic to induce an effective and long-lasting immune response against the target pathogen. In the case of live attenuated whole-cell bacterial vaccines, arriving at an optimal level of attenuation is particularly troublesome because overattenuation by reducing the amount or activity of virulence factors can result in a vaccine that is poorly immunogenic and/or unable to survive or replicate in a subject for a sufficient time after administration to induce an immune response.